“Ivacaftor” (INN, trade name Kalydeco) is being developed by Vertex pharmaceuticals for patients with a certain mutation of cystic fibrosis and it is classified as a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator. Ivacaftor is chemically known N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4oxoquinoline-3-carboxamide, and has the structure of Formula (I).

Ivacaftor was first disclosed in U.S. Pat. No. 7,495,103 and its process of preparation is disclosed as including reacting 4-Oxo-1,4-dihydro-quinoline-3-carboxylic acid of formula (II) with 2, 4 ditertiary butyl-5-nitro-phenol of formula (III) in presence of O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) and triethyl amine to obtain the compound of formula (I). The above synthetic process is illustrated as per the following Scheme-I

The process for the preparation of intermediate of formula (II) as per U.S. Pat. No. 7,495,103 is illustrated as per the following Scheme-II

The process for the preparation of intermediate of formula (III) as per U.S. Pat. No. 7,495,103 is illustrated as per the following Scheme-III

U.S. Pat. No. 8,476,442 discloses a process for the preparation of Ivacaftor by reacting compound of formula (X) with methylchloroformate in presence of a base to give a compound of formula (XI) and followed by nitration to get compound of formula (XII); later it has been reduced to give 2, 4 ditertiary butyl-5-amino-phenolic carboxylic methyl ester of formula (XV). 4-Oxo-1,4-dihydro-quinoline-3-carboxylic acid of formula (II) is condensed with a compound of formula (XV) to give a compound of formula (IX); further it is treated with sodium methoxide to give a crude Ivacaftor and it is recrystallized with isopropyl alcohol to give a pure compound of formula (I).
The above synthetic process of U.S. Pat. No. 8,476,442 is illustrated as per the following Scheme-IV

The process for the preparation of intermediate of formula of U.S. Pat. No. 8,476,442 is illustrated as per the following Scheme-V

The complexity of the known prior art processes for the preparation of the Ivacaftor and its intermediates of formulas (II) and (III) are:                a) Expensive as isomeric separation of intermediate (III) requires column chromatography which is not applicable on an industrial scale;        b) Polyphosphoric acid and POCl3 are used for cyclization of 4-hydroxyquinoline 3-carboxylic acid ethyl ester;        c) Both these reagents Polyphosphoric acid and POCl3 are toxic and very difficult to handle at plant scale;        d) Polyphosphoric acid and POCl3 are used in large quantities for the reaction, and subsequently large quantity of base is required for their neutralization; and        e) Large quantities of effluents are generated.        
There is consequently a need for an alternative method for the preparation of Ivacaftor and its intermediates which does not involves the problems described above. Such methods should be more industrially scalable, economic and should employ reagents that are cheaper, easier to handle and allow only desired compounds to be obtained with a high purity yields.